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Frascati international research criteria for HIV-associated neurocognitive disorders (HAND) are controversial; some investigators have argued that Frascati criteria are too liberal, resulting in a high false positive rate. Meyer et al. recommended more conservative revisions to HAND criteria, including exploring other commonly used methodologies for neurocognitive impairment (NCI) in HIV including the global deficit score (GDS). This study compares NCI classifications by Frascati, Meyer, and GDS methods, in relation to neuroimaging markers of brain integrity in HIV.
Two hundred forty-one people living with HIV (PLWH) without current substance use disorder or severe (confounding) comorbid conditions underwent comprehensive neurocognitive testing and brain structural magnetic resonance imaging and magnetic resonance spectroscopy. Participants were classified using Frascati criteria versus Meyer criteria: concordant unimpaired [Frascati(Un)/Meyer(Un)], concordant impaired [Frascati(Imp)/Meyer(Imp)], or discordant [Frascati(Imp)/Meyer(Un)] which were impaired via Frascati criteria but unimpaired via Meyer criteria. To investigate the GDS versus Meyer criteria, the same groupings were utilized using GDS criteria instead of Frascati criteria.
When examining Frascati versus Meyer criteria, discordant Frascati(Imp)/Meyer(Un) individuals had less cortical gray matter, greater sulcal cerebrospinal fluid volume, and greater evidence of neuroinflammation (i.e., choline) than concordant Frascati(Un)/Meyer(Un) individuals. GDS versus Meyer comparisons indicated that discordant GDS(Imp)/Meyer(Un) individuals had less cortical gray matter and lower levels of energy metabolism (i.e., creatine) than concordant GDS(Un)/Meyer(Un) individuals. In both sets of analyses, the discordant group did not differ from the concordant impaired group on any neuroimaging measure.
The Meyer criteria failed to capture a substantial portion of PLWH with brain abnormalities. These findings support continued use of Frascati or GDS criteria to detect HIV-associated CNS dysfunction.
Background: SMA is characterized by reduced levels of survival of motor neuron (SMN) protein from deletions and/or mutations of the SMN1 gene. While SMN1 produces full-length SMN protein, a second gene, SMN2, produces low levels of functional SMN protein. Risdiplam (RG7916/RO7034067) is an investigational, orally administered, centrally and peripherally distributed small molecule that modulates pre-mRNA splicing of SMN2 to increase SMN protein levels. Methods: SUNFISH (NCT02908685) is an ongoing multicenter, double-blind, placebo-controlled, operationally seamless study (randomized 2:1, risdiplam:placebo) in patients aged 2–25 years, with Type 2/3 SMA. Part 1 (n=51) assesses safety, tolerability, pharmacokinetics and pharmacodynamics of different risdiplam dose levels. Pivotal Part 2 (n=180) assesses safety and efficacy of the risdiplam dose level selected based on Part 1 results. Results: Part 1 results showed a sustained, >2-fold increase in median SMN protein versus baseline following 1 year of treatment. Adverse events were mostly mild, resolved despite ongoing treatment and reflected underlying disease. No drug-related safety findings have led to withdrawal (data-cut 06/17/18). SUNFISH Part 1 exploratory endpoint results and Part 2 study design will also be presented. Conclusions: To date, no drug-related safety findings have led to withdrawal. Risdiplam led to sustained increases in SMN protein levels.
Oats can be processed in a variety of ways ranging from minimally processed such as steel-cut oats (SCO), to mildly processed such as large-flake oats (old fashioned oats, OFO), moderately processed such as instant oats (IO) or highly processed in ready-to-eat oat cereals such as Honey Nut Cheerios (HNC). Although processing is believed to increase glycaemic and insulinaemic responses, the effect of oat processing in these respects is unclear. Thus, we compared the glycaemic and insulinaemic responses elicited by 628 kJ portions of SCO, OFO, IO and HNC and a portion of Cream of Rice cereal (CR) containing the same amount of available-carbohydrate (23 g) as the oatmeals. Healthy males (n 18) and females (n 12) completed this randomised, cross-over trial. Blood was taken fasting and at intervals for 3 h following test-meal consumption. Glucose and insulin peak-rises and incremental AUC (iAUC) were subjected to repeated-measures ANOVA using Tukey’s test (two-sided P<0·05) to compare individual means. Glucose peak-rise (primary endpoint, mean (sem) mmol/l) after OFO, 2·19 (sem 0·11), was significantly less than after CR, 2·61 (sem 0·13); and glucose peak-rise after SCO, 1·93 (sem 0·13), was significantly less than after CR, HNC, 2·49 (sem 0·13) and IO 2·47 (sem 0·13). Glucose iAUC was significantly lower after SCO than CR and HNC. Insulin peak rise was similar among the test meals, but insulin iAUC was significantly less after SCO than IO. Thus, the results show that oat processing affects glycaemic and insulinaemic responses with lower responses associated with less processing.
Introduction: Patients with advanced or end-stage illness frequently present to emergency departments (EDs), many of whom are in need of palliative care (PC). Emergency physicians have struggled in providing high quality care to these patients and there is a need to identify cost-effective PC interventions delivered in the ED to improve patient outcomes. The objective of this systematic review was to examine the effectiveness of ED-based PC interventions. Methods: A comprehensive search of nine electronic databases and grey literature sources was conducted to identify any comparative studies assessing the effectiveness of ED-based PC interventions to improve health outcomes of patients with advanced or end-stage illness. Two independent reviewers completed study selection, quality assessment, and data extraction. Differences were mediated via third-party adjudication. Relative risks (RR) with 95% confidence intervals (CIs) were calculated using a random effects model and heterogeneity (I2) was reported. Results: From 5882 potentially eligible citations, 12 studies were included. Two studies are currently on-going clinical trials, and as such, 10 studies were included in this analysis. The studies consisted of before-after studies (n = 5), RCTs (n = 4), and an observational cohort (n = 1). Interventions assessed among the included studies consisted primarily of ED-directed PC consultations (n = 6), while other studies assessed screening of patients with advanced or end-stage illness and PC needs (n = 2), education on PC for ED-staff (n = 1), and an ED-based critical care unit (n = 1). Infrequent reporting of important outcomes (e.g., Mortality, ED relapse) limited the ability of this review to conduct meaningful meta-analysis. There was no difference in patient mortality between two studies assessing ED-directed PC consultations (RR = 0.89; 95% CI: 0.71, 1.13; I2 = 0%). One before-after study (RR = 0.73; 95% CI: 0.47, 1.13) and two RCTs (RR = 2.19; 95% CI: 0.40, 11.92; I2 = 96%) did not identify significant differences in PC consultations intervention (implementation of ED-directed PC consultations) and control (usual care) patients. Conclusion: This review found limited evidence to support the recommendation of any particular ED-based intervention for patients presenting to the ED with advanced or end-stage illness. High quality studies and standardized outcome reporting are needed to better understand the impact of PC interventions in the ED setting.
Introduction: With an increasing proportion of patients in need of end-of-life (EOL) care presenting to the emergency department (ED), many of these patients may benefit from early palliative care (PC) referral. In fact, early PC referral is one of the Choosing Wisely ED recommendations in the USA. As such, there is a potential benefit to identifying patients with advanced or end-stage illness with PC needs. The objective of this systematic review is to identify and synthesize the available evidence regarding the existence and psychometric properties of screening tools to identify patients with advanced or end-stage illness and PC needs presenting to EDs. Methods: A comprehensive search of eight electronic databases and the grey literature was conducted. Studies assessing the ability of a screening instrument to identify ED patients with advanced or end-stage illness in need of PC were eligible for inclusion. Two independent reviewers completed study selection, quality assessment, and data extraction. Disagreements were resolved through third-party adjudication. Due to the significant heterogeneity, as well as inconsistent outcome reporting, a descriptive summary of the results was completed. Results: Once duplicates were removed, the title and abstracts of 3516 studies were screened, of which, 15 studies were included. Overall, 10 unique screening instruments were assessed across the studies. The most commonly assessed screening tool was the use of the modified surprise question (SQ), in which physicians were asked if they would be surprised if the patient died within a specified period of time. Only four of the included studies assessed the diagnostic or psychometric properties of the screening tools. One study reported that the modified SQ predicted PC consultation with 35% sensitivity, 89% specificity, and a negative predictive value of 97%. The proportion of patients identified with PC needs ranged from 12% to 73%, with studies utilizing the SQ reporting a range of 12% to 33%. Conclusion: A variety of screening tools are available to identify ED patients with advanced or end-stage illness who would benefit from a referral for PC. While the modified SQ was the most common instrument assessed and appears to be simple to implement, it is unclear if the diagnostic and psychometric properties of this tool are sufficiently robust to warrant widespread implementation.
Every four years leading researchers gather to survey the latest developments in all aspects of group theory. Initially held in St Andrews, these meetings have become the premier forum for group theory across the whole of the UK. Since 1981, the proceedings of 'Groups St Andrews' have provided a regular snapshot of the state-of-the-art in group theory and helped to shape the direction of research in the field. This volume contains papers from the 2017 meeting held in Birmingham. It includes expository articles from the invited speakers, and further surveys contributed by the participants. Topics include: generation of finite simple groups, block theory, fusion systems, algebraic groups, one-relator groups, geometric group theory, and Beauville groups.
Objectives: Studies of neurocognitively elite older adults, termed SuperAgers, have identified clinical predictors and neurobiological indicators of resilience against age-related neurocognitive decline. Despite rising rates of older persons living with HIV (PLWH), SuperAging (SA) in PLWH remains undefined. We aimed to establish neuropsychological criteria for SA in PLWH and examined clinically relevant correlates of SA. Methods: 734 PLWH and 123 HIV-uninfected participants between 50 and 64 years of age underwent neuropsychological and neuromedical evaluations. SA was defined as demographically corrected (i.e., sex, race/ethnicity, education) global neurocognitive performance within normal range for 25-year-olds. Remaining participants were labeled cognitively normal (CN) or impaired (CI) based on actual age. Chi-square and analysis of variance tests examined HIV group differences on neurocognitive status and demographics. Within PLWH, neurocognitive status differences were tested on HIV disease characteristics, medical comorbidities, and everyday functioning. Multinomial logistic regression explored independent predictors of neurocognitive status. Results: Neurocognitive status rates and demographic characteristics differed between PLWH (SA=17%; CN=38%; CI=45%) and HIV-uninfected participants (SA=35%; CN=55%; CI=11%). In PLWH, neurocognitive groups were comparable on demographic and HIV disease characteristics. Younger age, higher verbal IQ, absence of diabetes, fewer depressive symptoms, and lifetime cannabis use disorder increased likelihood of SA. SA reported increased independence in everyday functioning, employment, and health-related quality of life than non-SA. Conclusions: Despite combined neurological risk of aging and HIV, youthful neurocognitive performance is possible for older PLWH. SA relates to improved real-world functioning and may be better explained by cognitive reserve and maintenance of cardiometabolic and mental health than HIV disease severity. Future research investigating biomarker and lifestyle (e.g., physical activity) correlates of SA may help identify modifiable neuroprotective factors against HIV-related neurobiological aging. (JINS, 2019, 25, 507–519)
Approximately 70% of the 30 000 known bee (Hymenoptera) species and most flower-visiting, solitary wasps (Hymenoptera) nest in the ground. However, nesting behaviours of most ground-nesting bees and wasps are poorly understood. Habitat loss, including nesting habitat, threatens populations of ground-nesting bees and wasps. Most ground-nesting bee and wasp studies implement trapping methods that capture foraging individuals, but provide little insight into the nesting preferences of these taxa. Some researchers have suggested that emergence traps may provide a suitable means by which to determine ground-nesting bee and wasp abundance. We sought to evaluate nest-site selection of ground-nesting bees and wasps using emergence traps in two study systems: (1) planted wildflower enhancement plots and fallow control plots in agricultural land; and (2) upland pine and hammock habitat in forests. Over the course of three years (2015–2017), we collected 306 ground-nesting bees and wasps across all study sites from emergence traps. In one study, we compared captures per trap between coloured pan traps and emergence traps and found that coloured pan traps captured far more ground-nesting bees and wasps than did emergence traps. Based on our emergence trap data, our results also suggest ground-nesting bees and wasps are more apt to nest within wildflower enhancement plots than in fallow control plots, and in upland pine habitats than in hammock forests. In conclusion, emergence traps have potential to be a unique tool to gain understanding of ground-nesting bee and wasp habitat requirements.
Background: Longitudinal data on health-related quality of life (HRQOL) and fatigue in paediatric Duchenne muscular dystrophy (DMD) are limited. Recently, fatigue was reported to be the greatest predictor of poor HRQOL in paediatric DMD. Understanding the trajectory of HRQOL and its relationship with fatigue may facilitate the development of improved therapeutic strategies. Our objective was to describe three-year changes in HRQOL and fatigue in children with DMD. Methods: Patients identified via the Canadian Neuromuscular Disease Registry received mailed questionnaires (2013–2016). HRQOL was assessed using the PedsQLTM GCS and NMM domains, and fatigue was assessed using the MFS domain (patient- and parent-report). Mean three-year change in scores were computed. Pearson correlations were computed between three-year change in HRQOL and fatigue. Results: Mean decline in MFS scores for patient- and parent-reports were 1.03 and 1.19, respectively. Mean decline in GCS scores for patient- and parent-report were 1.75 and 4.13, respectively. Mean change in NMM scores for patient- and parent-report were 0.72 and -8.36, respectively. Change in MFS score was associated with changes in GCS (r=0.72, p<0.001) and NMM scores (r=0.84, p<0.001) by patient-report. Conclusions: Children with DMD experience worse fatigue and HRQOL over time. Parents perceive a greater decline in HRQOL over time compared to patients.
Background: When measuring young Duchenne Muscular Dystrophy (DMD) patients’ health-related quality of life (HRQoL), parent-proxy reports are heavily relied on. Therefore, it is imperative that the relationship between parent-proxy and child self-report HRQoL is understood. This study examined the level of agreement between children and their parent-proxy rating of the child’s HRQoL. Methods: We used FOR-DMD clinical trial baseline data. HRQoL, measured using the PedsQL inventory, was reported by 178 parent and child (ages 4 to 7 years) dyads. Intracorrelation coefficients (ICC) measured absolute agreement while paired t-tests determined differences in the average HRQoL ratings between groups. Results: The level of agreement between child and parent-proxy ratings of HRQoL was poor for the generic PedsQL scale (ICC: 0.29) and its subscales; and, similarly low for the neuromuscular disease module (ICC:0.16). On average, parents rated their child’s HRQoL as poorer than the children rated themselves in all scales except for psychosocial and school functioning. Conclusions: Child and parent-proxy HRQoL ratings are discordant in this study sample, as occurs in other chronic pediatric diseases. This should be taken into account when interpreting clinical and research HRQoL findings in this population. Future studies should examine reasons for parents’ perception of poorer HRQoL than that reported by their children.
Background: Spinal Muscular Atrophy (SMA) is an autosomal recessive neurodegenerative disease. In June 2017, Health Canada approved Nusinersen, currently the only available drug for SMA. Since 2016, patients in Ontario have been treated clinically with Nusinersen through different access programs. Methods: Retrospective case series of patients with SMA treated clinically with Nusinersen in Ontario, describing clinical characteristics and logistics of intrathecal Nusinersen administration. Results: Twenty patients have been treated across four centres. To date, we have reviewed 8 cases at one centre (seven SMA Type I, one SMA Type II). Age at first dose ranged from 3-156 months and disease duration 9-166 months. Patients had received 4-7 doses at last evaluation. Three patients with scoliosis (2 with spinal rods) required fluoroscopy-guided radiologist administration, and 4 required general anesthesia. No complications/adverse events were reported. At last follow up, 5/8 families reported improved daily activities. Of 5 patients with baseline and follow up motor function testing, 3 demonstrated improved scores. One patient died due to respiratory decline at age 9 months, despite improved motor outcome scores. Conclusions: We describe the first Canadian post-marketing experience with Nusinersen. Timely dissemination of this information is needed to guide clinicians, hospital administrators, and policy-makers.
Background: The goal was to understand factors leading to prolonged wait times for neurological assessment of children with new onset seizures. A second objective was to develop an innovative approach to patient flow through and achieve a reduction in waiting times utilizing limited resources.
Audit of the referrals, flow through, wait times
Identification of bottlenecks
Development of triaging strategy:
Suspected Febrile seizures and non-epileptic events;
Suspected benign and absence epilepsies;
Suspected other Focal epilepsies, generalized epilepsies, epilepsy under 2 years
Initiation of early telephone contact and support
Development of a ketogenic diet
Results: Using a triaging strategy and focusing on timely access to investigations, wait times for clinic evaluations were shortened despite larger numbers of referrals (mean wait time reductions from 179 to 91 days). Limiting factors such increase in referral numbers, attrition in support staff, interfered with sustainability of reduced wait times achieved in the initial phase of the program. Conclusions: This pilot study highlights the effectiveness of an innovative triaging strategy and improvements in patient flow through in achieving the goals of reduction in wait times for clinical evaluation and timely investigations to improve care for children with new onset seizures. Insights into limitations of such strategies and factors determining sustainability are discussed.
Nighttime eating is often associated with a negative impact on weight management and cardiometabolic health. However, data from recent acute metabolic studies have implicated a benefit of ingesting a bedtime snack for weight management. The present study compared the impact of ingesting a milk snack containing either 10 (BS10) or 30 g (BS30) protein with a non-energetic placebo (BS0) 30 min before bedtime on next morning metabolism, appetite and energy intake in mildly overweight males (age: 24·3 (sem 0·8) years; BMI: 27·4 (sem 1·1) kg/m2). Next morning measurements of RMR, appetite and energy intake were measured using indirect calorimetry, visual analogue scales and an ad libitum breakfast, respectively. Bedtime milk ingestion did not alter next morning RMR (BS0: 7822 (sem 276) kJ/d, BS10: 7482 (sem 262) kJ/d, BS30: 7851 (sem 261) kJ/d, P=0·19) or substrate utilisation as measured by RER (P=0·64). Bedtime milk ingestion reduced hunger (P=0·01) and increased fullness (P=0·04) during the evening immediately after snack ingestion, but elicited no effect the next morning. Next morning breakfast (BS0: 2187 (sem 365) kJ, BS10: 2070 (sem 336) kJ, BS30: 2582 (sem 384) kJ, P=0·21) and 24 h post-trial (P=0·95) energy intake was similar between conditions. To conclude, in mildly overweight adults, compared with a non-energetic placebo, a bedtime milk snack containing 10 or 30 g of protein does not confer changes in next morning whole-body metabolism and appetite that may favour weight management.
At the QEII Health Sciences Centre Emergency Department (ED) in Halifax, Nova Scotia, advanced care paramedics (ACPs) perform procedural sedation and analgesia (PSA) for many indications, including orthopedic procedures. We have begun using ACPs as sedationists for emergent upper gastrointestinal (UGI) endoscopy. This study compares ACP-performed ED PSA for UGI endoscopy and orthopedic procedures in terms of adverse events, airway intervention, vasopressor requirement, and PSA medication use.
A data set was built from an ED PSA quality control database matching 61 UGI endoscopy PSAs to 183 orthopedic PSAs by propensity scores calculated using age, gender, and the American Society of Anesthesiologists (ASA) classification. Outcomes assessed were hypotension (systolic BP<100 mm Hg or a 15% decrease from baseline), hypoxia (SaO2<90%), apnea (>30 sec), vomiting, arrhythmias, death, airway intervention, vasopressor requirement, and PSA medication use.
UGI endoscopy patients experienced hypotension more frequently than orthopedic patients (OR=4.11, CI: 2.05-8.22) and required airway repositioning less often (OR=0.24, CI: 0.10-0.59). They received ketamine more frequently (OR=15.7, CI: 4.75-67.7) and fentanyl less often (OR=0.30, CI: 0.15-0.63) than orthopedic patients. Four endoscopy patients received phenylephrine, and one required intubation. No patient died in either group.
In ACP-led sedation for UGI endoscopy and orthopedic procedures, adverse events were rare with the notable exception of hypotension, which was more frequent in the endoscopy group. Only endoscopy patients required vasopressor treatment and intubation. We provide preliminary evidence that ACPs can manage ED PSA for emergent UGI endoscopy, although priorities must shift from pain control to hemodynamic optimization.
Prevalence of skin sores and scabies in remote Australian Aboriginal communities remains unacceptably high, with Group A Streptococcus (GAS) the dominant pathogen. We aim to better understand the drivers of GAS transmission using mathematical models. To estimate the force of infection, we quantified the age of first skin sores and scabies infection by pooling historical data from three studies conducted across five remote Aboriginal communities for children born between 2001 and 2005. We estimated the age of the first infection using the Kaplan–Meier estimator; parametric exponential mixture model; and Cox proportional hazards. For skin sores, the mean age of the first infection was approximately 10 months and the median was 7 months, with some heterogeneity in median observed by the community. For scabies, the mean age of the first infection was approximately 9 months and the median was 8 months, with significant heterogeneity by the community and an enhanced risk for children born between October and December. The young age of the first infection with skin sores and scabies reflects the high disease burden in these communities.
The Molonglo Observatory Synthesis Telescope (MOST) is an 18000 m2 radio telescope located 40 km from Canberra, Australia. Its operating band (820–851 MHz) is partly allocated to telecommunications, making radio astronomy challenging. We describe how the deployment of new digital receivers, Field Programmable Gate Array-based filterbanks, and server-class computers equipped with 43 Graphics Processing Units, has transformed the telescope into a versatile new instrument (UTMOST) for studying the radio sky on millisecond timescales. UTMOST has 10 times the bandwidth and double the field of view compared to the MOST, and voltage record and playback capability has facilitated rapid implementaton of many new observing modes, most of which operate commensally. UTMOST can simultaneously excise interference, make maps, coherently dedisperse pulsars, and perform real-time searches of coherent fan-beams for dispersed single pulses. UTMOST operates as a robotic facility, deciding how to efficiently target pulsars and how long to stay on source via real-time pulsar folding, while searching for single pulse events. Regular timing of over 300 pulsars has yielded seven pulsar glitches and three Fast Radio Bursts during commissioning. UTMOST demonstrates that if sufficient signal processing is applied to voltage streams, innovative science remains possible even in hostile radio frequency environments.